Cholesterol is a lipid of the sterol family which plays an essential role in numerous biochemical processes.
It is a major component of animal cell membranes which contributes to their stability and to the maintaining of their structure by inserting between the phospholipids. Indeed, cholesterol stiffens the membrane by preventing gelling thereof since it prevents fatty acid crystallization and also decreases membrane permeability to water-soluble molecules. By inserting into membranes, cholesterol also allows the formation of lipid rafts which are areas essential to the anchoring of functional proteins.
Moreover, cholesterol is also found in neurons, where it enables neurotransmitter synthesis by exocytosis and therefore nerve message propagation. It is directly involved in the formation of beta-amyloid peptides, and therefore in the pathogenesis of Alzheimer's disease. An association between atherosclerosis and Alzheimer's disease has also been demonstrated (Mikael Simons and al., “Cholesterol depletion inhibits the generation of b-amyloid in hippocampal neurons”, Proc. Natl. Acad. Sci. USA; Vol. 95, pp. 6460-6464, May 1998, Neurobiology.)
Cholesterol metabolism is also a precursor of numerous molecules, for instance steroid hormones (cortisol, cortisone and aldosterone), steroid sex hormones (progesterone, estrogens and testosterone), vitamin D3, heme A, prenylated and farnesylated proteins, ubiquinone or coenzyme Q10, dolichol, the nuclear factor NF kappa B, the Tau protein and bile salts.
Cholesterol is carried in the blood by transport systems with very different roles, namely LDL lipoproteins (low-density lipoproteins) and HDL lipoproteins (high-density lipoproteins).
HDL cholesterol is considered to be protective with respect to cardiovascular diseases and is frequently indicated as being “good cholesterol”.
Cholesterol-transporting LDLs penetrate into the arterial wall and are then taken up by the monocytes and macrophages residing in this arterial wall and also by the smooth muscle cells. This results in an excessive lipid load in the macrophages and smooth muscle cells which are then converted into foam cells responsible for the processes of atherosclerosis and corresponding to the first stage of atheromatous plaque formation. It is therefore a question of “bad cholesterol”.
Atheroma is defined by the World Health Organization as a “variable combination of changes in the intima of large and medium caliber arteries consisting of focal accumulations of lipids, complex carbohydrates, blood and calcium deposits associated with medial changes”. Atheroma is responsible for the majority of cardiovascular diseases and is the principal cause of morbidity and mortality in industrialized countries. Atheroma begins with the formation of a “fatty streak”, a simple linear deposit of fat with no effect on blood flow, located between the endothelium and media of the artery. Over time, this streak can become bigger, and become loaded with lipids, fibrinogen, platelets and other blood cells, and calcium, so as to constitute the “atheromatous plaque”. Said plaque becomes more or less large and can reduce the caliber of the artery sufficiently to reduce its flow rate.
There are two types of complications: the first, which evolves over the long term, is due to its slow growth, increasingly impairing the passage of blood until it completely prevents it by blockage. The second, which is rapid and responsible for the acute complications, consists of damage to or rupture of the endothelium: the breach formed is then blocked by an aggregation of blood platelets and the formation of a blood clot which can rapidly totally block the vessel. This clot can also detach and block further downstream. The plaque can also partially detach and also block the artery, or more rarely, release its content and produce a cholesterol embolism. Finally, the dilation of the arterial wall induced by the increase in volume of the plaque can result in the formation of an aneurysm, with a risk of rupture.
The pharmaceutical class most widely used for preventing atheroma is the statins, which aim to reduce the circulating lipid and LDL cholesterol level, in addition to an appropriate diet. However, the advantage and usefulness of statins has for a while been sharply criticized by some researchers and clinicians who assert that statins, after analysis of controversial since contradictory statistical trials, do not provide patients with the expected therapeutic benefit. Added to this implication are the harmful and even sometimes dramatic side effects which have been identified and have, in certain cases, led to withdrawal from the market.
The other drug treatments proposed today are:                platelet aggregation inhibitors such as aspirin or clopidogrel, which are supposed to decrease the formation of clots from the atheromatous plaque;        antihypertensive drugs, such as angiotensin-converting enzyme inhibitors.        
The pharmaceutical treatments which exist at the current time are therefore solely aimed at decreasing the risks associated with atheroma. None of the drugs which exist on the market directly attacks the atheromatous plaque.
When the vital prognosis is brought into play, the treatment is surgical or endovascular. It aims to restore the arterial lumen, to irrigate the oxygen-deprived area or to eliminate the arterial aneurysm. Among these techniques, mention may be made of angioplasty, unblocking by endarterectomy, and bypass.
Finally, the principal means for combating atheroma and complications thereof still remains today behavioral in nature: giving up smoking, developing physical activity, controlling blood pressure, correcting a dyslipidaemia, controlling diabetes, diet.
Thus, it must be noted that there has for a long time clearly been an unsatisfied need for treatment and/or prevention of atheroma.
Various approaches have however been attempted, without it having been possible for a new solution to be retained. HDL cholesterol in particular began to be studied in 1975 when researchers demonstrated the relationship between high HDL cholesterol levels and a decrease in the incidence of cardiovascular diseases (Rye K. A. 2013. High density lipoprotein structure, function, and metabolism: a new Thematic Series. J. Lipid Res. 54:(8) 2031-2033). The positive results of these studies have encouraged the development of treatments aimed at increasing HDL cholesterol levels, among which inhibitors of the CETP (cholesterol ester transfer protein) enzyme, which were the very first agents developed and evaluated on a large scale, specifically for this purpose, will be retained. However, none of these treatments has made it possible to reduce the occurrence of cardiovascular events.
Finally, there is still no drug available on the market that is capable of effectively inducing an increase in HDL cholesterol level in patients, in particular because the mechanisms involved are still today far from being elucidated. In particular, there is no drug available on the market that is capable of effectively and actively combating diseases that can be treated and/or prevented by an increase in the HDL cholesterol level. In addition, there is a constant need for a drug capable of combating atherosclerosis, in particular atheromatous plaque formation.